Many CD8+ T cells in the melanoma microenvironment are becoming progressively dysfunctional yet remain highly proliferative, according to researchers.

The ecology of immune cell populations within tumor microenvironments importantly contributes to tumor responses to immunotherapy but the details of these interactions are not yet completely understood. Using RNA sequencing data, authors of a study published in Cell report that many CD8+ T cells in the melanoma microenvironment are becoming progressively dysfunctional states yet remain highly proliferative—and that the abundance of these cells is associated with tumor recognition.

T-cell receptor (TCR) and single-cell RNA sequencing (scRNA-seq) data for 25 patients with melanoma revealed a large compartment of CD8+ immune T cells within the tumor microenvironment that exhibit progressive states of T-cell dysfunction while continuing to proliferate and differentiate, researchers reported in Cell.1

The findings are the latest evidence of how CD8+ T cells behave in tumor microenvironments.1,2

“Our data demonstrate thatCD8[+] T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment,” wrote Ton N. Schumacher, PhD, of the Oncode Institute, Netherlands Cancer Institute in Amsterdam, and coauthors.1 “[W]e observed large variability in the abundance of dysfunctional T cells even between treatment-naive tumors at the same organ site. This indicates that immune infiltrates of human melanomas show a heterogeneity that is largely intrinsic, independent of prior treatment or metastatic site.”

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TCR analysis and scRNA-seq data revealed a gradient of T-cell dysfunction and showed that proliferation was “most profound” during the early stages of dysfunction, the study authors reported.1

“In line with previous observations, our data show that the dysfunctional T cell pool does not form a discrete cell population but is part of a wide differentiation spectrum,spanning from transitional through early dysfunctional toward highly dysfunctional T cells,” the authors reported.1 “This proposed differentiation trajectory was not a patient-specific phenomenon but rather a universal feature of CD8[+] T cells within melanoma. Notably, while this trajectory was also observed in [non-small cell lung cancer], it appears more abundant in melanoma patients.… This suggests a differential impact of the tumor microenvironment on the development of T-cell dysfunction across tumor types, conceivably reflecting differential availability of antigen or differential exposure to inhibitory factors.”

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